Compounds having anti-hepatitis C virus effect

ABSTRACT

It is found out that compounds represented by the formula (I):                    
     wherein R 1  is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and R 2  and R 3  taken together with the adjacent carbon atom form an optionally substituted heterocyclic group having one or more of oxo and/or thioxo; have an HCV RNA-dependent RNA synthase inhibitory effect.

TECHNICAL FIELD

The present invention relates to a treating agent against hepatitis C,in detail an anti-hepatitis C virus agent, a nucleic acid polymeraseinhibitor, and a RNA-dependent RNA polymerase inhibitor.

BACKGROUND ART

It is supposed that there are one to two hundred million people infectedwith hepatitis C virus (hereafter called as HCV) worldwide, and over 1.5million people infected with HCV in Japan. Approximately 50% of thembecome chronic hepatitis, and approximately 20% thereof become livercirrhosis or hepatocellular carcinoma after 30 years or more of theinfection. In Japan, twenty and several thousand people die every yeardue to hepatocellular carcinoma caused by HCV infection. At present,interferon α is used widely as a treating agent against hepatitis C,however, percentage of successful treatment is only 20% to 30% and itsside effect is strong. It is expected to develop a more useful and moresafety treating agent.

The anti-HCV agents are targeted on protease, RNA helicase,RNA-dependent RNA polymerase, and the like, and as the RNA-dependent RNApolymerase inhibitor known are cerulenin, gliotoxin, and dioxobutyricacid ((1) Antiviral Res., 41, 65 (1999), (2) Antiviral Ther., 3 (Suppl3), 99 (1998), (3) WO00/06529).

On the other hand, as an acylthiazolidinedione derivative similar to acompound of the present invention, a compound wherein the acyl group isa substituted benzoyl group is described in (1) Strukt. Mekh. DeistviyaFiziol. Aktiv. Veschestv (1972) 92-92, (2) Khim. Geterotsikl. Soedin.(1972), (11), 1492-1495. However, in these references a concrete medicaluse is not described. Furthermore, a compound wherein the acyl group isa substituted heteroarylcarbonyl group is not; described therein at all.

DISCLOSURE OF INVENTION

The development of a treating agent against hepatitis C, especially anHCV RNA-dependent RNA polymerase inhibitor, is expected.

It is found that an acylthiazolidinedione derivative and the like havean HCV RNA-dependent RNA polymerase inhibitory effect.

That is, the present invention relates to:

(1) A treating agent against hepatitis C virus which contains as anactive ingredient a compound of the formula (I), a tautomer, a prodrug,a pharmaceutically acceptable salt, or a solvate thereof:

wherein R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R² and R³ taken together withthe adjacent carbon atom form an optionally substituted heterocyclicgroup having one or more of oxo and/or thioxo,

(2) A treating agent against hepatitis C virus as described in (1)wherein R¹ is optionally substituted heteroaryl or optionallysubstituted aryl; R² and R³ taken together with the adjacent carbon atomform a group of the formula (A):

wherein A¹ and A³ are each independently oxygen atom or sulfur atom; A²and A⁴ are each independently —O—, —S—, or —NR⁴— wherein R⁴ is hydrogen,optionally substituted alkyl, optionally substituted acyl, optionallysubstituted aryl, or optionally substituted aralkyl,

(3) A treating agent against hepatitis C virus as described in (2)wherein A¹ is oxygen atom; A² is —NH—; A¹ and A⁴ are sulfur atom,

(4) A compound of the formula (II):

wherein R¹ is optionally substituted carbocyclic group or optionallysubstituted heterocyclic group; A¹ and A³ are each independently oxygenatom or sulfur atom; A² is —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl, provided that when R¹ isoptionally substituted aryl, R⁴ is hydrogen or optionally substitutedalkyl; A⁴ is —S—; and provided that the following compounds are excludedwherein A¹ is oxygen atom, A² is —NEt-, A³ is sulfur atom, and R¹ is4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl,4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl;A¹ is oxygen atom, A² is —NH—, A³ is sulfur atom, and R¹ is2-thiocarboxyphenyl or 2-carboxyphenyl; and A¹ is oxygen atom, A² is—NH—, A¹ is oxygen atom, and R¹ is 2-carboxyphenyl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(5) A compound of (4) wherein R¹ is optionally substituted heteroaryl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(6) A compound of (4) wherein R¹ is non-substituted heteroaryl orheteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, trityl,alkoxyalkoxy, cyanoallylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl,carboxy or alkoxycarbonyl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(7) A compound of (5) or (6) wherein R¹ is optionally substituted5-membered heteroaryl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(8) A compound of (5) or (6) wherein R¹ is optionally substituted furyl,optionally substituted t-hienyl, optionally substituted pyrrolyl,optionally substituted imidazolyl, optionally substituted oxazolyl,optionally substituted isoxazolyl, optionally substituted triazolyl,optionally substituted oxadiazolyl, optionally substituted tetrazolyl,optionally substituted pyridyl, optionally substituted benzofuryl,optionally substituted pyrimidinyl, optionally substituted pyrazinyl, oroptionally substitutec(thiazolyl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(9) A compound of (4) wherein R¹ is optionally substituted aryl;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(10) A compound of any one of (4) to (9) wherein A² is —NH—;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(11) A compound of any one of (4) to (10) wherein A¹ is oxygen atom; A³is sulfur atom;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(12) A compound of any one of (4) to (9) wherein A¹ is oxygen atom; A²is —NH—; A³ is sulfur atom; A⁴ is —S—;

a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof,

(13) A pharmaceutical composition which contains as an active ingredienta compound of any one of (4) to (12), a tautomer, a prodrug, apharmaceutically acceptable salt, or a solvate thereof,

(14) A pharmaceutical composition of (13) as a treating agent againsthepatitis C,

(15) A pharmaceutical composition of (13) as an anti-hepatitis C virusagent,

(16) A pharmaceutical composition of (13) as a nucleic acid polymeraseinhibitor,

(17) A pharmaceutical composition of (13) as a RNA-dependent RNApolymerase inhibitor,

(18) A method of treating hepatitis C comprising administration of atreating agent against hepatitis C of (1),

(19) Use of a compound of (1) for the preparation of a treating agentagainst hepatitis C,

The present invention has found that a compound of the formula (I), atautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof:

wherein R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R² and R³ taken together withthe adjacent carbon atom form an optionally substituted heterocyclicgroup having one or more of oxo and/or thioxo; exhibits an inhibitoryeffect against nucleic acid polymerase, in detail an inhibitory effectagainst RNA-dependent RNA polymerase, and inhibits the increase of HCV,whereby to provide a treating agent against HCV containing thesecompounds or the like.

A characteristic of the compounds used in the present invention is thatthe group represented by R¹, and an optionally substituted heterocyclicgroup having one or more of oxo and/or thioxo which is formed by R² andR³ taken together with the adjacent carbon atom are substituted on agroup of the formula:

Especially, as a compound of the formula (1) the following cases arepreferred.

wherein R¹ is optionally substituted heteroaryl or optionallysubstituted aryl,

wherein R¹ is optionally substituted heteroaryl,

wherein R¹ is non-substituted heteroaryl or heteroaryl optionallysubstituted with alkyl, alkoxy, hydroxy, halogen, trityl, alkoxyalkyl,cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl, carboxy, oralkoxycarbonyl,

wherein R¹ is optionally substituted 5-membered heteroaryl,

wherein R¹ is optionally substituted furyl, optionally substitutedthienyl, optionally substituted pyrrolyl, optionally substitutedimidazolyl, optionally substituted oxazolyl, optionally substitutedisoxazolyl, optionally substituted triazolyl, optionally substitutedoxadiazolyl, optionally substituted tetrazolyl, optionally substitutedpyridyl, optionally substituted benzofuryl, optionally substitutedpyrimidinyl, optionally substituted pyrazinyl, or optionally substitutedthiazolyl,

wherein R¹ is optionally substituted 5-membered aryl,

wherein R² and R³ taken together with the adjacent carbon atom form agroup of the formula (A):

wherein A¹ and A³ are each independently oxygen atom or sulfur atom; A²and A⁴ are each independently —O—, —S—, or —NR⁴— wherein R⁴ is hydrogen,optionally substituted alkyl, optionally substituted acyl, optionallysubstituted aryl, or optionally substituted aralkyl.

In a group shown by the above (A), preferred are those.

wherein A¹ and A³ are each independently oxygen atom or sulfur atom; A²is —NR⁴— wherein R⁴ is hydrogen, optionally substituted alkyl,optionally substituted acyl, optionally substituted aryl, or optionallysubstituted aralkyl; A⁴ is —S—,

wherein A¹ is oxygen atom; A² is —NH—; A¹ is sulfur atom; A⁴ is —S—,

wherein A² is —NH—,

wherein A¹ is oxygen atom; A³ is sulfur atom, or

wherein A¹ is oxygen atom; A² is —NH—; A³ is sulfur atom; A⁴ is —S—.

Especially, preferable is a compound of the formula (II):

wherein R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; A¹ and A³ are eachindependently oxygen atom or sulfur atom; A² is —NR⁴— wherein R⁴ ishydrogen, optionally substituted alkyl, optionally substituted acyl,optionally substituted aryl, or optionally substituted aralkyl, providedthat when R¹ is an optionally substituted aryl, R⁴ is hydrogen oroptionally substituted alkyl; A⁴ is sulfur atom.

Each term employed alone or in combination with other terms has thefollowing means.

The term “carbocyclic group” means cycloalkyl, cycloalkenyl, or aryl.Especially, aryl is preferred.

The term “cycloalkyl” means a cycloalkyl having 3 to 10 carbon atoms.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cyclopentyl andcyclohexyl are preferred.

The term “cycloalkenyl” means a cycloalkenyl having 3 to 10 carbonatoms. Examples of cycloalkenyl include 1-cyclopropenyl, 1-cyclobutenyl,1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl, 1-cyclooctenyl, andthe like. 1-Cyclopentenyl and 1-cyclohexenyl are preferred.

The term “aryl” means monocyclic or condensed ring aromatic carbocyclicgroup having 6 to 14 carbon atoms. Examples of aryl include phenyl,1-naphtyl, 2-naphtyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, and thelike. Phenyl, 1-naphtyl, and 2-naphtyl are preferred.

The term “herterocyclic group” for R¹ means heteroaryl and non-aromaticherterocyclic group. Especially, heteroaryl is preferred.

The term “heteroaryl” herein used means a 5 to 7 membered aromaticheterocyclic group which contains one or more of nitrogen, oxygen, andsulfur atoms in the ring, or an aromatic cyclic group fused with one ormore aromatic carbocyclic group or other aromatic heterocyclic group.The “heteroaryl” may have a bond ragical at any substitutable position,for example at a carbon or nitrogen atom in the aromatic heterocyclicgroup or aromatic carbocyclic group. Examples of the heteroaryl includefuryl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl),pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g.,2-pyridyl, 3-pyridyl, 4-pyridyl), oxazolyl (e.g., 2-oxazolyl,4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),isothiazolyl (e.g., 3-isothiazolyl, 4-isotbiazolyl, 5-isothiazolyl),imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), triazolyl(e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl),oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g.,1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), pyrazolyl (e.g., 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl), furazanyl (e.g., 3-furazanyl), pyridazinyl(e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl(e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,7-indolyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl,4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl,7-benzo[b]thienyl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl,4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl),benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl), quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), cinnolinyl(e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl,7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl,4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl,6-quinoxalinyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl,6-phthalazinyl), pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl,6-pteridinyl, 7-pteridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl,3-acridinyl, 4-acridinyl, 9-acridinyl), phenazinyl (e.g., 1-phenazinyl,2-phenazinyl), phenothiazinyl (e.g., 1-phenothiazinyl, 2-phenothiazinyl,3-phenothiazinyl, 4-phenothiazinyl), and the like.

“5-Membered heteroaryl” is preferred. Examples of the 5-memberedheteroaryl include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g.,2-thienyl 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl(e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl), triazolyl (e.g.,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl(e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g., 1-tetrazolyl,2-tetrazolyl, 5-tetrazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl), furazanyl (e.g., 3-furazanyl), and the like. Especially,are preferred furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), oxazolyl(e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), triazolyl (e.g.,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl(e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g., 1-tetrazolyl,2-tetrazolyl, 5-tetrazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl,4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl),pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyrazinyl (e.g., 2-pyrazinyl), thiazolyl (e.g., 2-thiazolyl,4-thiazolyl, 5-thiazolyl), and the like.

The term “non-aromatic heterocyclic group” herein used means anon-aromatic heterocyclic group which contains one or more hetero atomsselected from the group consisting of nitrogen, oxygen, and sulfur atomsin the ring, and the group has a bond radical at any substitutableposition. Examples of the non-aromatic heterocyclic group include1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl,4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl,2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, oxazolinyl,and the like. Further, “non-aromatic heterocyclic group” may besaturated or unsaturated.

Further, “carbocyclic group” and “heterocyclic group” for R¹ may befused additionally with a carbocycle or heterocycle. The term“carbocycle” means carbocycle corresponding to the above mentioned“carbocyclic group”. Examples of carbocycle include cyclobutane,cyclopentane, cyclohexane, cycloheptane, benzene, naphthalene, and thelike. The term “heterocycle” means heterocycle corresponding to theabove mentioned “heterocyclic group”. Examples of heterocycle arepyrrolidine, piperadine, oxolane, 1,3-dioxolane, 1,4-dioxolane,thiolane, thiophen, furan, pyrrole, pyridine, and the like.

These carbocycle and heterocycle may be fused additionally withcarbocycle or heterocycle.

Examples of the above “carbocyclic group” or “heterocyclic group” whichare fused with carbocycle or heterocycle are as follows.

The term “heterocyclic group having one or more oxo or thioxo” meansheterocyclic group having 1 to 3 oxo or thioxo at any possible positionin the ring. Especially, 5- or 6-membered heterocyclic group having oxoor thioxo at a neighboring position of the bond radical is preferred andexemplified below.

wherein A¹ is each independently oxygen atom or sulfur atom; A⁵ is eachindependently —O—, —S—, —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl, or —CH₂—, provided that one ormore of A⁵ is —O—, —S—, —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl.

Among the above, preferable is a group represented by the formula (A):

and more preferable is that wherein A¹ and A³ are each independentlyoxygen atom or sulfur atom; A² and A⁴ are each independently —O—, —S—,or —NR⁴— wherein R⁴ is hydrogen, optionally substituted alkyl,optionally substituted acyl, optionally substituted aryl, or optionallysubstituted aralkyl.

Especially, preferable is a compound of the formula (II):

wherein R¹ is optionally substituted carbocyclic group or optionallysubstituted heterocyclic group; A¹ and A³ are each independently oxygenatom or sulfur atom; A² is —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl, provided that when R¹ isoptionally substituted aryl, R⁴ is hydrogen or optionally substitutedalkyl; A⁴ is —S—; and provided that the following compounds are excludedwherein A¹ is oxygen atom, A² is —NEt-, A³ is sulfur atom, and R¹ is4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl,4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl;A¹ is oxygen atom, A² is —NH—, A³ is sulfur atom, and R¹ is2-thiocarboxyphenyl or 2-carboxyphenyl; and A¹ is oxygen atom, A² is—NH—, A³ is oxygen atom, and R¹ is 2-carboxyphenyl.

Substituents of “optionally substituted alkyl” and “optionallysubstituted acyl” include, for example, alkyl, alkenyl, alkynyl,cycloalkyl, halogen, hydroxy, carboxy, formyloxy, formyl, haloformyl,oxalo, mercapto, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl,sulfino, sulfo, sulfamoyl, sulfoamino, optionally substituted amino,cyano, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato,hydroxyamino, carbamoyl, nitroso, nitro, hydrazino, azide, ureido,amidino, guanidino, and the like. Especially, cycloalkyl, halogen,hydroxy, carboxy, optionally substituted amino, cyano, and the like arepreferred. And unsubstituted one is preferred.

These substituents may be at 1 to 3 any substitutable position(s) in theabove mentioned alkyl and the above mentioned acyl.

Substituents of “optionally substituted carbocyclic group”, “optionallysubstituted heterocyclic group”, “optionally substituted aryl”,“optionally substituted aralkyl” and “optionally substituted heteroaryl”include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, halogen,hydroxy, carboxy, formyloxy, formyl, haloformyl, oxalo, mercapto,thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo,sulfamoyl, sulfoamino, optionally substituted amino, cyano, isocyano,cyanato, isocyanato, thiocyanato, isothiocyanato, hydroxyamino,carbamoyl, nitroso, nitro, hydrazino, azide, ureido, amidino, guanidino,trityl, alkoxyalkyl, cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl,cyanoalkyl, carboxy, and alkoxycarbonyl, and the formula: —Z¹-Z² whereinZ¹ is a single bond, —O—, —C(═O)—O—, —O—C(═O)—, —C(═O)—, —C(═O)—C(═O)—,—C(═O).C(═O)—O—, —CH₂—C(═O)—, —S—, —SO₂—, —SO—, —C(═S)—, —NH—, —NZ³—,—NH—C(═O)—, —C(═O)—NH—, —NZ³—C(═O)—, —C(═O)—NZ³—, —N═N—, —NH—C(═O)—O—,—NH—SO₂—, —SO₂—NH—, —NZ³—SO₂— or —SO₂—NZ³—; Z² and Z³ are eachindependently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,optionally substituted aminoalkyl, carbocyclic group optionallysubstituted with alkyl, hydroxy or halogen, heterocyclic groupoptionally substituted with alkyl, hydroxy or halogen, arylalkyloptionally substituted with alkyl, hydroxy or halogen, orheteroarylalkyl optionally substituted with alkyl, hydroxy or halogen,and the like. Especially, preferred are alkyl, alkoxy, hydroxy, halogen,trityl, alkoxyalkoxy, cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl,cyanoalikyl, carboxy and alkoxycarbonyl. And unsubstituted one ispreferred.

These substituents may be at 1 to 5 any substitutable position(s) in theabove mentioned carbocyclic group, the above mentioned heterocyclicgroup, the above mentioned aryl, the above mentioned aralkyl and theabove mentioned heteroaryl.

The term “alkyl” herein used means a straight or branched chain alkylhaving 1 to 8 carbon atom(s). Examples of alkyl include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neo-pentyl, t-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl,n-nonanyl, and the like.

The term “alkenyl” herein used means a straight or branched chainalkenyl having 2 to 8 carbon atoms and one or more double bonds.Examples of the alkenyl include vinyl, 1-propenyl, 2-propenyl,isopropenyl, and the like.

The term “lower alkynyl” herein used means a straight or branched chainalkynyl having 2 to 8 carbon atoms and one or more triple bond. Examplesof the alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, and the like.

Alkyl consisted in “alkoxy” is defined as the above “alkyl”, examples ofalkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, and the like. Especially, methoxy and ethoxy arepreferred.

The term “acyl” herein used means carbonyl substituted with theabove-mentioned “alkyl” and the above-mentioned “aryl”. Examples of acylinclude acetyl, propyonyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, hexanoyl, octanoyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and thelike. Especially, acetyl and benzoyl are preferred.

The term “halogen” herein used means fluoro, chloro, bromo, and iodo.

The term “haloalkyl” herein used means the above-mentioned “alkyl” whichis one or more substituted with halogen. Examples of the haloalkylinclude chloromethyl, fluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 1,1-difluoroethyl, trichloromethyl,2,2,2-trichloroethyl, 1,1-dichloroethyl, and the like.

The term “hydroxyalkyl” herein used means the above-mentioned “alkyl”which is one or two substituted with hydroxy. Examples of thehydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1,1-dihydroxyethyl, 1,2-dihydroxyethyl, 1,2-dihydroxy-n-propyl, and thelike.

The term “aminoalkyl” herein used means the above-mentioned “alkyl”which is one or two substituted with amino. Examples of the aminoalkylinclude aminomethyl, 1-aminoethyl, 2-aminoethyl, 1,1-diaminoethyl,1,2-diaminoethyl, 1,2-diamino-n-propyl, and the like.

Substituents of “optionally substituted amino” and “optionallysubstituted aminoalkyl” include, for example, the above-mentioned“alkyl”, the above-mentioned “arylalkyl”, the above-mentioned“carbocyclic group”, the above-mentioned “heterocyclic group”, theabove-mentioned “heteroarylalkyl”, and the like. They may be mono- ordi-substituted with these substituents. Further, when they aredi-substituted with “alkyl”, may form a ring taken together nitrogenatom of amino group.

Examples of “optionally substituted amino” include amino, methylamino,dimethylamino, methylethylamino, diethylamino, pyrrolidino, piperidino,phenylmethylamino, isopropylamino, diisopropylamino, and the like.

Examples of “optionally substituted aminoalkyl” include aminomethyl,dimethylaminomethyl, methylaminomethyl, methylethylaminomethyl,diethylaminomethyl, pyrrolidinomethyl, piperidinomethyl,phenylmethylaminomethyl, isopropylaminomethyl, diisopropylaminomethyl,and the like.

The term “alkoxyalkoxy” herein used means the above-mentioned alkoxysubstituted with the above-mentioned alkoxy, examples of alkoxyalkoxyinclude methoxymethoxy, ethoxymethoxy, n-propoxymethoxy,isopropoxymethoxy, n-butoxymethoxy, isobutoxymethoxy,tert-butoxymethoxy, and the like. Especially, methoxymethoxy andethoxymethoxy are preferred.

The term “cyanoarylalkoxy” herein used means the above-mentioned alkoxysubstituted the above-mentioned aryl substituted with cyano, examples ofcyanoarylalkoxy include 2-cyanobenzyloxy and the like.

The term “cyanoalkoxy” herein used means the above-mentioned alkoxysubstituted with cyano, examples of cyanoalkoxy include3-cyano-n-propoxy and the like.

The term “cyanoalkyl” herein used means the above-mentioned alkylsubstituted with one to two cyano, examples of cyanoalkyl includecyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1,1-dicyanoethyl,1,2-dicyano-n-propyl, 3-cyano-n-propyl, and the like.

The term “alkoxycarbonyl” herein used means the carbonyl substitutedwith the above-mentioned “alkoxy”, examples of alkoxycarbonyl includemethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.Especially, methoxycarbonyl and ethoxycarbonyl are preferred.

BEST MODE FOR CARRYING OUT THE INVENTION

The preparation of the compound of the formula (I) is explained asfollows.

wherein R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R² and R³ taken together withthe adjacent carbon atom form an optionally substituted heterocyclicgroup having one or more of oxo and/or thioxo; L is leaving group (e.g.,alkoxy, halogen).

In the above preparation, the compound of the formula (I) is obtained byreacting the compound of the formula (P-1) with the compound of theformula (P-2) in the presence of a base.

Examples of the compound of the formula (P-1) include(substitute(d)benzoic acid ester (e.g., benzoic acid methyl ester,benzoic acid ethyl ester, o-hydroxybenzoic acid methyl ester,o-hydroxybenzoic acid ethyl ester, m-chlorobenzoic acid methyl ester,p-methylbenzoic acid ethyl ester), (substituted)cycloalkanecarboxylicacid ester (e.g., cyclopropanecarboxylic acid ethyl ester,cyclobutanecarboxylic acid ethyl ester, cyclohexanecarboxylic acid ethylester, 4-carboxycyclohexanecarboxylic acid ethyl ester,(substituted)cycloalkenecarboxylic acid ester (e.g.,1-cyclohexene-1-carboxylic acid ethyl ester,4-chloro-1-cyclohexene-1-carboxylic acid ethyl ester),(substituted)heteroarylcarboxylic acid ester (e.g.,5-methyloxazole-2-carboxylic acid ethyl ester, oxazole-2-carboxylic acidethyl ester, furan-2-carboxylic acid ethyl ester, triazole-3-carboxylicacid ethyl ester, 5-methylisoxazole-3-carboxylic acid ethyl ester,isoxazole-3-carboxylic acid ethyl ester, 5-methyloxadiazole-2-carboxylicacid ethyl ester, tetrazole-5-carboxylic acid ethyl ester,thiophene-2-carboxylic acid ethyl ester, 5-methylfuran-2-carboxylic acidethyl ester, benzofuran-2-carboxylic acid ethyl ester,furan-3-carboxylic acid ethyl ester, thiophene-3-carboxylic acid ethylester, 4-methylisoxazole-5-carboxylic acid ethyl ester,isoxazole-5-carboxylic acid ethyl ester, 5-bromofuran-2-carboxylic acidethyl ester, pyrrole-2-carboxylic acid ethyl ester,1-methylimidazole-2-carboxylic acid ethyl ester,2-trityltriazole-5-carboxylic acid ethyl ester),(substituted)non-aromatic heterocyclecarboxylic acid ester (e.g.,morpholine-2-carboxylic acid ethyl ester), (substituted)benzoyl halide(e.g., benzoyl chloride, benzoyl bromide, o-hydroxybenzoyl chloride,o-hydroxybenzoyl bromide, m-chlorobenzoyl chloride, p-methylbenzoylchloride), (substituted)cycloalkanecarbonyl halide (e.g.,cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride,cyclohexanecarbonyl chloride, 4-carboxycyclohexanecarbonyl chloride),(substituted)cycloalkenecarbonyl halide (e.g., 1-cyclohexene-1-carbonylchloride, 4-chloro-1-cyclohexene-1-carbonyl chloride),(substituted)heteroarylcarbonyl chloride (e.g.,5-methyloxazole-2-carbonyl chloride, oxazole-2-carbonyl chloride,furan-2-carboxylic acid ethyl ester, triazole-3-carbonyl chloride,5-methylisoxazole-3-carbonyl chloride, isoxazole-3-carbonyl chloride,5-methyloxadiazole-2-carbonyl chloride, tetrazole-5-carbonyl chloride,thiophene-2-carbonyl chloride, 5-methylfuran-2-carbonyl chloride,benzofuran-2-carbonyl chloride, furan-3-carbonyl chloride,thiophene-3-carbonyl chloride, 4-methylisoxazole-5-carbonyl chloride,isoxazole-5-carbonyl chloride, 5-bromofuran-2-carbonyl chloride,pyrrole-2-carbonyl chloride, 1-methylimidazole-2-carbonyl chloride,2-trityltriazole-5-carbonyl chloride), (substituted)non-aromaticheterocyclecarbonyl halide (e.g., morpholine-2-carbonyl chloride).

Examples of the compound of the formula (P-2) include the formula:

wherein A¹ is each independently oxygen atom or sulfur atom; A⁵ is eachindependently —O—, —S—, —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl, or —CH₂—; provided that one ormore of A⁵ is —O—, —S—, or —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl. More concrete examples arerhodanine, 3-pyridazinone, pyrazolone, 2-methylpyridone,2-imidazolidinethione, 2-imidazolidone, 3-indolinone, barbituric acid,and the like.

As a base, can be used sodium alcoholate (e.g., sodium methylate, sodiumethylate), n-butyl lithium, LDA (lithium diisopropylamide), sodiumhydride, LHMDS (lithium bis(trimethylsilyl)amide) or the like.Especially, n-butyl lithium, LDA and LHMDS are preferred. The base maybe selected depending on the kind of substitutent(s) on the grouprepresented by the formula R¹ in the compound of the formula (P-2) orthe characteristic of the compound of the formula (P-2).

In the present preparation, it is preferred to react at a lowtemperature depending on the kind of base, for example, at −10 to 0° C.For example, when as a base used is n-butyl lithium, LDA, or LHMDS, itis preferred to react at −80 to −60° C.

Furthermore, the above reaction may be conducted as that to the compoundof the formula (P-2) is added a base at low temperature (e.g., −80 to−60° C.), and the reaction mixture is stirred at the same temperaturefor several minutes to several hours, followed by warming to 0° C. toroom temperature, then cooled again, and to the reaction mixture isadded the compound of the formula (P-1).

In the above-mentioned reaction, the substitutent(s) on the grouprepresented by the formula R¹ of the compound of the formula (P-1) maybe protected and deprotected if necessary.

Furthermore, the substituent(s) of a group represented by R¹ of thecompound of the formula (P-1) can be introduced thereto before or afterthe above-mentioned reaction. Especially, when the group represented bythe formula: —R¹ is an aromatic group, the introduction of substituentis easy. For example, an aromatic compound substituted with nitro can beobtained by nitration using mixed acid or the like. Moreover, anaromatic compound substituted with amino can be obtained by reductionusing tin or the like in hydrochloric acid. Moreover, an aromaticcompound substituted with hydroxy can be obtained by diazotizationfollowed by basic solvolysis. Furthermore, an aromatic compoundsubstituted with alkoxy can be obtained by reacting a diazo derivativewith an alcohol. Furthermore, an aromatic compound substituted withhalogen can be obtained by Sandmeyer reaction, i.e. reaction of a diazoderivative with a copper(II) salt (e.g., CuCl₂, CuBr₂). Moreover, anaromatic compound substituted with halogen can be obtained too by directchlorination or the like. Halogen can be introduced into a desiredposition by using these methods.

Alkyl, alkenyl and acyl can be directly introduced to an aromatic groupby Friedel-Crafts reaction using anhydrous aluminium chloride and thelike, and an alkylation reagent, alkenylation reagent, or acylationreagent.

Compounds used in the present invention include regioisomers thereof.Regioisomer means a cis or trans isomer of the compound of the formula(I) or (II). Furthermore, the present invention includes tautomersthereof. Tautomer means a keto tautomer or enol tautomer of the compoundof the formula (I) or (II). For example, the regioisomer and tautomer ofthe compound of the formula (I) or (II) are described as follows.

wherein each symbol is as defined above.

Furthermore, the compound of the formula (I′) and (II′) of the presentinvention include R-form and S-form described below.

Moreover, most of NMR data are described as corresponding to thestructure of the above-mentioned the formula (I) or (II), depending onthe measuring condition in later-mentioned examples.

Prodrug is included in the compound of the present invention. Prodrug isa derivative of the compound having a group which can be decomposedchemically or metabolically, and such a prodrug is a compound accordingto the present invention which becomes pharmaceutically active bysolvolysis or under a physiological condition in vivo. The method ofselection and manufacture of appropriate prodrug derivatives isdescribed in, for example. Design of Prodrugs, Elsevier, Amsterdam,1985.

The present invention relates to a treating agent against hepatitis Cvirus, thus preferable is a prodrug for transferring to liver as atarget. The prodrug for transferring to liver is preferably that havinghigher lipophilicity, which can be achieved by modifying carboxyl,hydroxy, or amino of a compound.

For example, in case of the compound of the formula (I) or (II) havingcarboxy, exampled is an ester derivative which is prepared by reactingan acidic compound and a suitable alcohol. Especially preferable esterderivatives as prodrug are alkyl ester (e.g., methyl ester, ethyl ester,n-propyl ester, isoprpyl ester, n-butyl ester, isobutyl ester,tert-butyl ester, benzyl ester) having 1 to 30 carbon atom(s) optionallysubstituted with one or more substituent(s) selected from a groupconsisted of carboxy, dimethylamino, alkylcarbonyloxy (e.g.,—OCO(CH₃)₃), alkyloxycarbonyloxy (e.g., —OCOOC₂H₅), and aryl.

Furthermore, in case of the compound of the formula (I) or (II) havinghydroxy, exampled is an acyloxy derivative which is prepared by reactinga compound having hydroxy and a suitable acyl halide or suitable acidanhydride. Especially preferable acyloxy derivatives as prodrug arealkylcarbonyloxy (e.g., —OCOC₂H₅, —OCO(tert-Bu), —OCOC₁₅H₃₁,—OCOCH₂CH₂COONa, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂ having 1 to 30 carbonatom(s) optionally substituted with one or more substituent(s) selectedfrom a group consisted of COONa, COOK, amino, carboxy, anddimethylamino, arylcarbonyloxy (e.g., —OCOPh(2-COONa)) optionallysubstituted with COONa, and the like.

Furthermore, in case of the compound of the formula (I) or (II) havingamino, exampled is an amide derivative which is prepared by reacting acompound having amino and a suitable acyl halide or suitable mixed acidanhydride. Especially preferable amide derivatives as prodrug arealkylcarbonylamino (e.g., —NHCO(CH₂)₂₀CH₃, —NHCOCH(NH₂)CH₃) having 1 to30 carbon atom(s) optionally substituted with amino.

Examples of the compound of the formula (I) or (II) or a prodrug thereofinclude alkali metal salt (e.g., lithium salt, sodium salt, potassiumsalt,), alkaline-earth metal salt (e.g., calcium salt), salt of organicbase (e.g., tromethamine, trimethylamine, triethylamine, 2-aminobutane,tert-butylamine, diisopropylethylamine, n-butylmethylamine,cyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine,methylbenzylamine, dibenzylamine, N,N-methylbenzylamine,2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylenemethylamine,diphenylbenzylamine, triphenylamine, 1-naphtylamine, 1-aminoanthracene,2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine, orpyridine), or amino acid salt (e.g., lysine salt, arginine salt).

For example, the compound of the formula (II) in the present inventioncan be in the following structure:

wherein A¹ is oxygen atom; A² is —NH—; other symbols are as definedabove.

wherein A¹ is oxygen atom; A² is —NH—; other symbols are as definedabove; M⁺ is a metal ion, e.g., Li⁺, Na⁺, K⁺, ½Ca²⁺, NH₄ ⁺.

The term “solvate” used herein means a solvate of the compound of theformula (I) or (II), a tautomer, a prodrug, or a pharmaceuticalacceptable salt thereof, for example, including solvates with alcohol(e.g., ethanol), hydrates, and the like. As hydrates exampled aremonohydrate, dihydrate, and the like.

The compounds of the formula (I) or (II) have an inhibitory activityagainst nucleic acid polymerase, especially, against nucleic acidpolymerase of virus. The structure of nucleic acid polymerase isdifferent depending on virus, however, in WO 00/06528, WO 98/41196, andthe like it is described that various nucleic acid polymerase have acommon function, thus inhibitors thereof can be used commonly. Forexample, a compound having an inhibitory activity against nucleic acidpolymerase of a certain virus has an inhibitory activity against nucleicacid polymerase of other virus. A compound of the present invention hasnot only an inhibitory activity against a HCV RNA-dependent RNApolymerase, but also an inhibitory activity against a BVDV RNA-dependentRNA polymerase, thus which can be used as an inhibitor against severalnucleic acid polymerase.

Especially, the compound of the present invention is usuful asRNA-dependent RNA polymerase inhibitor. Therefore, a compound of thepresent invention can be used for treating diseases related to virushaving RNA-dependent RNA polymerase. Such viruses include that belongingto the family Flaviviridae (e.g., hepatitis C virus (HCV), dengue virus,Japanese encephalitis virus), virus belonged the family Togaviridae(e.g., Sindbis virus, bovine virus diarrhea virus (BVDV; bovine virusdiarrhea virus)). Therefore, a pharmaceutical composition containing thecompound of the formula (I) or (II) is usuful as an anti-flavivirusagent and anti-togavirus agent. Furthermore, the compound of the formula(I) or (II) has a strong inhibitory effect especially against HCVRNA-dependent RNA polymerase, and a pharmaceutical compositioncontaining the compound can be an effective anti-HCV agent or treatingagent against hepatitis C.

The compound used in the present invention can be administered orally orparenterally. In case of oral administration, a compound used in thepresent invention can be used as any one of usual medication, forexample, solid medicine such as tablet, powder, granule, capsule;solution; oily suspending agent; or syrup agent, or liquid medicine suchas elixir agent. In case of parenteral administration, a compound usedin the present invention can be used as aqueous or oily suspensionparenteral injection, nasal drop. In the preparation of them, can beused optionally, usual vehicle, binding agent, lubricant, aqueoussolvent, oilness solvent, emulsifier, suspending agent, preservatives,stabilizer, and the like.

The medication of the compound used in the present invention is preparedby combining (e.g., mixing) an therapeutically effective dose of thecompound with a pharmaceutically acceptable carrier or diluent. Themedication of a compound used in the present invention is prepared byknown methods using well-known, easily obtainable components.

In case of manufacturing a pharmaceutical composition of the compoundused in the present invention, active ingredients are admixed or dilutedwith a carrier, or they are contained in a carrier in the form ofcapsule, sacheier, paper, or another container. In case of functioning acarrier as a diluent, the carrier is a solid, semi-solid, or liquidmaterial which functions as a medium, and they may be formulated totablet, pill, powder medicine, intraoral medicine, elixir agent,suspending agent, emulsifier, dissolving agent, syrup agent, aerosolagent (solid in liquid medium), and ointment. Such a formulation maycontain up to 10% of an active compound. It is preferred to prepare aformulation of compounds used in the present invention prior toadministration.

Any suitable carrier well known by those skilled in the art may be usedfor the formulation. In such a formulation, a carrier is in the form ofsolid, liquid, or a mixture thereof. For instance, the compound of thepresent invention is dissolved into 4% dextrose/0.5% sodium citrateaqueous solution so as to be 2 mg/mL concentration for intravenousinjection. Solid formulation includes powder, tablet, and capsule. Solidcarrier consists of one or more of material(s) for serving also asfragrant, lubricant, dissolving agent, suspension, binder, tabletdisintegrator, capsule. A tablet for oral administration contains adisintegrator such as corn starch, alginic acid and the like, and/or abinder such as gelatin, acacia and the like, and a lubricant such asmagnesium stearate, stearic acid, talc and the like, and a suitableexcipient such as calcium carbonate, sodium carbonate, lactose, calciumphosphate.

In a powder medicine, a carrier is a finely pulverized solid which isblended with finely pulverized active ingredients. In a tablet, activeingredients are admixed with a carrier having required binding power ina suitable ratio, and it is solidified in a desired shape and size.Powder medicine and tablet contain about 1 to about 99% by weight of theactive ingredients being novel compounds according to the presentinvention. Examples of suitable solid carriers include magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth gum, methyl cellulose, sodiumcarboxymethylcellulose, low-melting wax, and cocoa butter.

An axenic liquid formulation contains suspending agent, emulsifier,syrup agent, and elixir agent. Active ingredients may be dissolved orsuspended into a pharmaceutically acceptable carrier such as sterilewater, a sterile organic solvent, a mixture thereof and the like. Activeingredients may be dissolved frequently into a suitable organic solventsuch as propylene glycol aqueous solution. When finely pulverized activeingredients are dispersed into aqueous starch, sodiumcarboxylmethylcellulose solution, or suitable oil, the othercompositions can be prepared.

The dosage varies with the conditions of the disease, administrationroute, age and body weight of patient. In case of oral administration,the dosage can generally be between 0.05 to 3000 mg/kg/day, preferably0.1 to 1000 mg/kg/day for an adult, which is provided in divisions ifnecessary. Furthermore, in case of parenteral administration, the dosagecan generally be between 0.01 to 1000 mg/kg/day, preferably 0.05 to 500mg/kg/day. for an adult.

Furthermore, the pharmaceutical composition of the present invention mayinclude another treating agent against hepatitis C (e.g., interferon,protease inhibitor, nucleic acid polymerase inhibitor, immunoactivableagent,). Especially, such a treating agent preferably is that having adifferent effect mechanism, producing a synergistic effect with thecompound of the present invention, from that of an agent of the presentinvention (e.g., protease inhibitor) is preferred.

Moreover, the present invention includes a treating method againsthepatitis C characterized by administrating a treating agent againsthepatitis C containing the compound of the present invention and use ofthe compound of the present invention for preparing a treating agentagainst hepatitis C.

EXAMPLE

The following examples are provided to further illustrate the presentinvention and are not to be construed as limiting the scope thereof.Abbreviations described below are used in the following examples.

Me methyl; Et: ethyl; LHMDS: lithium bis(trimethylsilyl)amide; THFtetrahydrofuran; n-BuLi: n-butyllithium

Example 15-[1-Hydroxy-1-(5-methyloxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-1)

To a solution of rhodanine (0.266 g, 2 mmol) in THF (10 mL) was addeddropwise a n-hexane solution of lithium bis(trimethylsilyl)amide (1 M, 4mL, 4 mmol) at −78° C. After the reaction mixture was stirred at thesame temperature for 30 min, a solution of 5-methyloxazole-2-carboxylicacid ethyl ester (0.26 g, 1.7 mmol) in THF (5 mL) was added thereto. Thereaction mixture was stirred at −78° C. for 1 h and at 0° C. for 2 h,and adjusted to pH 3 by addition of 10% aqueous solution of citric acid.The resulting solid was filtered, washed with water and ethyl acetatesuccessively, and was suspended into 2 mol/L, hydrochloric acid. To thesuspension was added ethyl acetate and the solution was extracted twotimes with ethyl acetate. The extract was washed with water and brinesuccessively, treated with active carbon, and dried. The solvent wasevaporated, and the obtained crystals were filtered and washed withn-hexane/ethyl acetate=3/1 (v/v) to give the title compound (0.21 g).

m.p.: 243-245° C. (decomposition) Anal. Calcd for C₈H₆N₂O₃S₂: C, 39.66;H, 2.50; N, 11.56; S, 26.47. Found: C, 39.81; H, 2.54; N, 11.25; S,26.51. NMR(d₆-DMSO) δ: 2.43(3H, d, J=1.8 Hz), 7.34(1H, d, J=1.8 Hz).

Example 25-[1-(Furan-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-2)

To a solution of rhodanine (0.615 g, 4.6 mmol) in THF (10 mL) was addeddropwise a n-hexane solution of n-butyl lithium (1.5 M, 6.2 mL, 9.3mmol) at −78° C. for 15 min. After the reaction mixture was stirred atthe same temperature for 15 min and warmed gradually to 0° C., and thenstirred for additional 30 min. The reaction mixture was cooled to −78°C. again and a solution of 2-furoyl chloride (0.66 g, 5.1 mmol) in THF(5 mL) was added thereto. The reaction mixture was stirred at sametemperature for 30 min and at room temperature for 1 h, adjusted to pH 3by addition of 2 mol/L hydrochloric acid, and extracted with ethylacetate. The extract was dried and concentrated, and the residue waspartitioned between ethyl acetate and aqueous solution of sodiumhydrogen carbonate and stirred for 30 min. The obtained sodium salt wasfiltered, washed with water and ethyl acetate successively, andsuspended into excess of 2 mol/l, hydrochloric acid. The suspension wasstirred for 30 min, extracted with ethyl acetate, and dried. The solventwas evaporated, and the obtained crystals were filtered and washed withn-hexane/ethyl acetate (v/v, 3/1) to give the title compound (0.18 g).

m.p.: 230-235° C. (decomposition) Anal. Calcd for C₈H₅NO₃S₂ 0.125C₄H₈O₂: C, 42.84; H, 2.54; N, 5.88; S, 26.92. Found: C, 42.61; H, 2.44;N, 5.90; S, 26.64. NMR(d₆-DMSO) δ: 6.61(1H, dd, J=3.3, 1.2 Hz), 7.24(1H,d, J=3.3 Hz), 7.94(1H, d, J=1.2 Hz), 13.3(1H, brs).

The following compounds were synthesized in similar manners describedabove.

Example 35-[-Hydroxy-1-(thophen-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-3)

m.p.: 213-220° C. (decomposition) Anal. Calcd for C₈H₅NO₂S₃: C, 39.49;H, 2.07; N, 5.76; S, 39.53. Found: C, 39.54; H, 2.08; N, 5.80; S, 39.31.NMR(d₆-DMSO) enol-type/keto-type=7/1 Enol-type δ: 7.24-7.40(1H, m),7.93(1H, brs), 8.02(1H, brs). Keto-type δ: 6.58(1H, brs), 7.24-7.40(11H,m), 8.14(1H, brs), 8.22(1H, brs).

Example 4 5-[1-Hydroxy-1-(thiophen-2-yl)]methylenethiazolidine-2,4-dione(Compound I-4)

m.p.: 203-204° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₅NO₃S₂: C, 42.28; H, 2.22; N,6.16; S, 28.22. Found: C, 42.35; H, 2.35; N, 6.16; S, 28.11.NMR(d₆-DMSO) enol-type/keto-type=1/1 Enol-type δ: 7.28-7.38(1H, m),7.67(1H, brs), 8.17-8.25(1H, m). Keto-type δ: 6.47(1H, s), 7.28-7.38(1H,m), 8.05(1H, d, J=4.2 Hz),8.17-8.25(1H, m).

Example 5 5-[1-Hydroxy-1-(thiophen-2-yl)]methylenethiazolidine-2,4-dionesodium salt (Compound I-5)

m.p.: 205-207° C. (decomposition) recrystallization solvent: ethanolAnal. Calcd for C₈H₄NO₃S₂Na 1.25H₂O: C, 35.37; H, 2.41; N, 5.16; Na,8.46, S, 23.64. Found: C, 35.21; H, 1.85; N, 5.14; Na, 5.70, S, 23.44.NMR(d₆-DMSO) enol-type/keto-type=1/1 Enol-type δ: 7.28-7.38(1H, m),7.69(1H, brs), 8.17-8.24(1H, m). Keto-type δ: 6.48(1H, s), 7.28-7.38(1H,m), 8.04(1H, brs), 8.17-8.24(1H, m).

Example 65-[1-Hydroxy-1-(3-methoxyphenyl)]methylenethiazolidine-2,4-dione(Compound I-6)

m.p.: 159-160° C. recrystallization solvent: methanol Anal. Calcd forC₁₁H₉NO₄S: C, 52.58; H, 3.61; N, 5.57, S, 12.76. Found: C, 52.47; H,3.39; N, 5.64; S, 12.68. NMR(d₆-DMSO) enol-type/keto-type=2/1 Enol-typeδ: 3.81(3H, s), 7.00-7.40(4H, m). Keto-type δ: 3.84(3H, s), 6.63(1H, s),7.00-7.70(4H, m).

Example 75-[1-Hydroxy-1-(3-hydroxyphenyl)]methylenethiazolidine-2,4-dione(Compound I-7)

m.p.: 237-239° C. (decomposition) recrystallization solvent: ethylacetate Anal. Calcd for C₁₀H₇NO₄S: C, 50.63; H, 2.97; N, 5.90, S, 13.52.Found: C, 52.33; H, 3.04; N, 5.88; S, 13.60. NMR(d₆-DMSO)enol-type/keto-type=4/1 Enol-type δ: 6.80-7.50(4H, m), 10.0(1H, brs).Keto-type δ: 6.51(1H, s), 6.80-7.50(4H, m), 9.68(1H, brs).

Example 8 5-[1-Hydroxy-1-(thiophen-3-yl)]methylenethiazolidine-2,4-dione(Compound I-8)

m.p.: 214-216° C. (decomposition) Anal. Calcd for C₈H₅NO₃S₂: C, 42.28;H. 2.22; N, 6.16; S, 28.22. Found: C, 42.21; H, 2.27; N, 6.19; S, 27.94.NMR(d₆-DMSO) enol-type/keto-type=2/1 Enol-type δ: 7.44(1H, d, J=4.5 Hz),7.79(1H, brs), 8.17(1H, brs). Keto-type δ: 6.42(1H, s), 7.58(1H, dd,J=1.8, 4.5 Hz), 7.73(1H, d, J=4.5 Hz), 8.74(1H, d, J=1.8 Hz).

Example 9 5-[1-(Furan-2-yl)-1-hydroxy]methylenethiazolidine-2,4-dione(Compound I-9)

m.p.: 141-142° C. recrystallization solvent: diisopropyl ether Anal.Calcd for C₈H₅NO₄S 0.25C₆H₁₄O 0.125H₂O: C, 47.74; H, 3.69; N, 5.86; S,13.42. Found: C, 47.76; H, 3.49; N, 5.80; S, 13.54. NMR(d₆-DMSO)enol-type/keto-type=7/1 Enol-type δ: 6.70-8.40(3H, m), 12.7(1H, brs).Keto-type δ: 6.21(1H, s), 6.70-8.40(3H, m), 12.5(1H, brs).

Example 105-[1-Hydroxy-1-(thiophen-2-yl)]methylene-3-methylthiazolidine-2,4-dione(Compound I-10)

m.p.: 153-154° C. recrystallization solvent: n-hexane/ethyl acetateAnal. Calcd for C₉H₇NO₃S₂ 0.125H₂O: C, 44.35; H, 3.00; N, 5.75; S,26.31. Found: C, 44.69; H, 2.78; N, 5.86; S, 26.31. NMR(d₆-DMSO)enol-type/keto-type=1/1 Enol-type δ: 3.00(3H, s), 7.27-7.40(1H, m),7.70(1H, brs), 8.20-8.26(1H, m). Keto-type δ: 3.10(3H, s), 6.49(1H, s),7.27-7.40(1H, m), 8.06(1H, brs), 8.20-8.26(1H, m).

Example 11 5-[1-Hydroxy-1-(2-me thoxyphenyl)]methylene-2-thioxothiazolidin-4-one (Compound I-11)

m.p.: 183-185° C. (decomposition) recrystallization solvent: diisopropylether Anal. Calcd for C₁₁H₉NO₃S₂: C, 49.42; H, 3.39; N, 5.24, S, 23.99.Found: C, 49.46; H, 3.51; N, 5.16; S, 23.71. NMR(d₆-DMSO) δ: 3.78(3H,s), 7.00(1H, t, J=8.4 Hz), 7.12(1H, d, J=8.4 Hz), 7.34(1H, d, J=6.3 Hz),7.46-7.52(1H, m).

Example 125-[1-Hydroxy-1-(2-methoxyphenyl)]methylenethiazolidine-2,4-dione(Compound I-12)

m.p.: 143-146° C. recrystallization solvent: diisopropyl ether Anal.Calcd for C₁₁H₉NO₄S: C, 52.58; H, 3.61; N, 5.57, S, 12.76. Found: C,52.52; H, 3.59; N, 5.55; S, 13.04. NMR(d₆-DMSO) enol-type/keto-type=4/1Enol-type δ: 3.77(3H, s), 6.92-7.70(4H, m). Keto-type δ: 3.86(3H, s),6.00(1H, s), 6.92-7.70(4H, m).

Example 135-[1-(Benzofuran-2-yl)-1-hydroxy]methylenethiazolidine-2,4-dione(Compound I-13)

m.p.: 275-278° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₁₂H₇NO₄S 0.125H₂O: C, 54.69; H,2.87; N, 5.32, S, 12.17. Found: C, 54.68; H, 2.49; N, 5.37; S, 12.18.NMR(d₆-DMSO) enol-type/keto-type=7/1 Enol-type δ: 7.34-8.22(5H, m).Keto-type δ: 6.45(1H, s), 7.34-8.22(5H, m).

Example 145-[1-(Benzofuran-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-14)

m.p.: 235-240° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₁₂H₇NO₃S₂: C, 51.97; H, 2.54; N,5.05, S, 23.12. Found: C, 51.98; H, 2.54; N, 4.89; S, 22.21.NMR(d₆-DMSO) δ: 7.30-7.84(5H, m), 7.95(1H, brs), 13.5(1H, brs).

Example 153-Carboxymethyl-5-[1-(furan-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-15)

m.p.: 237-240° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₁₀H₇NO₅S₂: C, 42.10; H. 2.47; N,4.91, S, 22.48. Found: C, 42.19; H, 2.57; N, 4.82; S, 22.03.NMR(d₆-DMSO) δ: 4.67(2H, s), 6.78(1HT, brs), 7.80(1H, brs), 8.07(1H,brs).

Example 163-Carboxymethyl-5-[1-(thiol)hen-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-16)

m.p.: 215-220° C. (decomposition) recrystallization solvent: diisopropylether Anal. Calcd for C₁₀H₇NO₄S₃: C, 39.86; H, 2.34; N, 4.65, S, 31.92.Found: C, 39.89; H, 2.43; N, 4.59; S, 31.42. NMR(d₆-DMSO) δ: 4.66(2H,s), 7.22(1H, brs), 7.87(1H, brs), 8.45(1H, brs).

Example 175-[1-Hydroxy-1-(2-hydroxyphenyl)]methylene-2-thioxothiazolidin-4-one(Compound I-17)

m.p.: 178-180° C. (decomposition) recrystallization solvent:n-hexane/diisopropyl ether Anal. Calcd for C₁₀H₇NO₃S₂: C, 47.42; H,2.79; N, 5.53, S, 25.32. Found: C, 47.30; H, 2.88; N, 5.57; S, 24.75.NMR(d₆-DMSO) δ: 6.80-6.90(2H, m), 7.25-7.35(1H, m), 7.50(1H, brs),12.0(1H, brs).

Example 185-[1-Hydroxy-1-(2-hydroxyphenyl)]methylenethiazolidine-2,4-dione(Compound I-18)

m.p.: 138-140° C. recrystallization solvent: n-hexane/ether Anal. Calcdfor C₁₀H₇NO₄S: C, 50.63; H, 2.97; N, 5.90, S, 13.52. Found: C, 50.41; H,3.00; N, 5.88; S, 13.64. NMR(d₆-DMSO) Enol-type δ: 6.80-6.90(2H, m),7.20-7.40(2H, m), 11.5(1H, brs). Keto-type δ: 6.15(1H, s), 6.90-7.00(2H,m), 7.50-7.80(2H, m), 11.3(1H, s).

Example 19 5-[1-(Furan-3-yl)-1-hydroxy]methylenethiazolidine-2,4-dione(Compound I-19)

m.p.: 201-204° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₅NO₄S 0.125C₄H₈O₂: C, 45.94;H, 2.72; N, 6.30; S, 14.43. Found: C, 45.83; H, 2.61; N, 6.49; S, 14.72.NMR(d₆-DMSO) enol-type/keto-type=3/Enol-type δ: 7.90(2H, brm), 8.35(1H,s). Keto-type δ: 6.16(1H, s), 6.89(1H, brm), 7.90(1H, brm), 8.79(1H, s).

Example 205-[1-(Furan-3-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-20)

m.p.: 178-180° C. (decomposition) recrystallization solvent:n-hexane/diisopropyl ether Anal. Calcd for C₈H₅NO₃S₂ 0.125H₂O: C, 41.86;H, 2.31; N, 6.10; S, 27.94. Found: C, 41.83; H, 2.36; N, 6.19; S, 27.95.NMR(d₆-DMSO) δ: 6.88(1H, m), 7.86(1H, m), 8.52(1H, m), 13.3(2H, brs).

Example 215-[1-Hydroxy-1-(pyrrol-2-yl)]methylene-2-thioxothiazolidin-4-one(compound I-21)

m.p.: 160-163° C. (decomposition) recrystallization solvent: diisopropylether NMR(d₆-DMSO) δ: 5.30-7.20(3H, m), 12.0(1H, brs), 13.0(1H, brs).

Example 225-[1-Hydroxy-1-(5-methylfuran-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-22)

m.p.: 195-198° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₉H₇NO₃S₂: C, 44.80; H, 2.92; N,5.80; S, 26.58. Found: C, 44.78; H, 2.90; N, 5.75; S, 26.28.NMR(d₆-DMSO) δ: 2.41(3H, s), 6.45(1H, d, J=3.0 Hz), 7.48(1H, d, J=3.0Hz), 13.4(2H, brs).

Example 235-[1-(5-Bromofuran-2-yl)-1-hydroxy-]methylene-2-thioxothiazolidin-4-one(Compound I-23)

m.p.: 205-210° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₄BrNO₃S₂ 0.1C₄H₈O₂0.25H₂O: C,31.80; H, 1.60; Br, 25.19; N, 4.42; S, 20.22. Found: C, 31.58; H, 1.45;Br, 25.27; N, 4.69; S, 20.39. NMR(d₆-DMSO) δ: 6.89(1H, d, J=3.6 Hz),7.68(1H, d, J=3.6 Hz), 13.3 (2H, brs).

Example 245-[1-Hydroxy-1-(5-methylfuran-2-yl)]methylenethiazolidine-2,4-dione(Compound I-24)

m.p.: 275-282° C. (decomposition) Anal. Calcd for C₉H₇NO₄S 2.25H₂O: C,43.63; H, 3.87; N, 5.65; S, 12.94. Found: C, 43.81; H, 3.03; N, 6.17; S,12.90. NMR(d₆-DMSO) enol-type/keto-type=2/1 Enol-type δ: 2.35(3H, s),6.29(1H, brm), 6.88(1H, m). Keto-type δ: 2.35(3H, s), 6.07(1H, s),6.94(1H, brm), 8.05(1H, m).

Example 255-[(5-Bromofuran-2-yl)-1-hydroxy]methylenethiazolidine-2,4-dione(Compound I-25)

m.p.: 217-220° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₄BrNO₄S: C, 33.12; H, 1.39;Br, 27.54; N, 4.83; S, 11.05. Found: C, 33.12; H, 1.41; Br, 27.29; N,4.86; S, 11.08. NMR(d₆-DMSO) enol-type/keto-type=2/1 Enol-type δ:6.93(1H, brs), 7.32(1H, brs). Keto-type δ: 6.20(1H[, s), 7.02(1H, d,J=3.6 Hz), 7.80(1H, d, J=3.6 Hz), 13.5(1H, brs).

Example 255-[1-[5-(4-Fluorobenzyl)furan]-2-yl]-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-25)

m.p.: 172-175° C. (decomposition) recrystallization solvent:n-hexane/diisopropyl ether Anal. Calcd for C₁₅H₁₀FNO₃S₂ 0.125H₂O: C,53.36; H, 3.06; F, 5.63; N, 4.15; S, 19.00. Found: C, 53.36; H, 3.00; F,5.60; N, 4.45; S, 19.06. NMR(d₆-DMSO) δ: 4.13(2H, s), 6.51(1H, d, J=3.6Hz), 7.12-7.38(4H, m), 7.41(1H, d, J=3.6 Hz).

Example 265-[1-Hydroxy-1-(5-methylisoxazol-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-26)

m.p.: 210-214° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₆N₂O₃S₂ 0.125H₂O: C, 39.29; H,2.58; N, 11.46; S, 26.23. Found: C, 39.29; H, 2.25; N, 11.48; S, 25.97.NMR(d₆-DMSO) δ: 2.49(3H, s), 6.67(1H, s), 13.1(1H, brs).

Example 275-[1-Hydroxy-1-(4-methylisoxazol-5-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-27)

m.p.: 230-234° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₆N₂O₃S₂: C, 39.66; H, 2.50; N,11.56; S, 26.47. Found: C, 39.61; H, 2.47; N, 11.58; S, 26.47.NMR(d₆-DMSO) δ: 2.32(3H, s), 7.33(1H, s), 12.9(1H, brs).

Example 295-[1-(Isoxazol-3-yl)1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-29)

m.p.: 210-215° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₇H₄N₂O₃S₂ 0.125H₂O: C, 36.45; H,1.86; N, 12.15; S, 27.82. Found: C, 36.67; H, 1.77; N, 11.77; S, 27.34.NMR(d₆-DMSO) δ: 5.87(1H, d, J=1.7 Hz), 8.64(1H, d, J=1.7 Hz).

Example 305-[1-(Isoxazol-5-yl)1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-30)

m.p.: 195-202° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₇H₄N₂O₃S₂ 0.063C₄H₈O₂ 0.125H₂O:C, 36.90; H, 2.03; N, 11.87; S, 27.17. Found: C, 36.95; H., 0.86; N,11.87; S, 27.16. NMR(d₆-DMSO) δ: 7.19(1H, d, J=1.8 Hz), 8.46(1H, d,J=1.8 Hz).

Example 315-[1-Hydroxy-1-(1-methylimidazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-31)

m.p.: 265-270° C. (decomposition) recrystallization solvent: methanolAnal. Calcd for C₈H₇N₃O₂S₂: C, 39.82; H, 2.92; N, 17.41; S, 26.58.Found: C, 39.70; H, 2.92; N, 17.23; S, 26.35. NMR(d₆-DMSO) δ: 4.04(3H,s), 7.70(1H, (I, J=1.5 Hz), 7.79(1H, (1, J=1.5 Hz),12.8(1H, brs).

Example 325-[1-Hydroxy-1-(2H-tetrazol-5-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-32)

m.p.: 188-193° C. (decomposition) recrystallization solvent:isopropanol/ethyl acetate Anal. Calcd for C₅H₃N₅O₂S₂ 0.33C₃H₈O 0.75H₂O:C, 27.43; H, 2.75; N, 26.66; S, 24.41. Found: C, 27.73; H, 2.74; N,26.21; S, 24.07. NMR(d₆-DMSO) δ: 5.55(1H, brs), 12.8(1H, brs).

Example 335-[1-Hydroxy-1-(1-trityl-1H-1,2,4-triazol-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-33)

m.p.: 216-220° C. (decomposition) recrystallization solvent: ethylacetate/methanol Anal. Calcd for C₂₆H₁₈N₄O₃S₂ 1.13H₂O: C, 61.17; H,4.16; N, 11.42; S, 13.07. Found: C, 61.07; H, 4.13; N, 11.71; S, 12.83.NMR(d₆-DMSO) δ: 7.05-7.50(15H, m), 7.91(1H, s).

Example 345-[1-Hydroxy-1-(1H-1,2,4-triazol-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-34)

m.p.: 285-290° C. (decomposition) recrystallization solvent: ethylacetate Anal. Calcd for C₆H₄N₄O₂S₂ 0.25C₄H₈O₂ 0.63H₂O: C, 31.73; H,2.36; N, 22.77; S, 26.07. Found: C, 31.57; H, 2.00; N, 22.77; S, 26.69.NMR(d₆-DMSO) δ: 8.79(1H, brs), 13.7(3H, brm).

Example 355-[1-Hydroxy-1-(pyrimidin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-35)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₅N₃O₂S₂ 0.15H₂O: C, 39.71; H, 2.21; N, 17.37; S, 26.50.Found: C, 39.87; H, 1.93; N, 17.22; S, 26.00. NMR(d₆-DMSO) δ: 7.36(1H,t, J=4.8 Hz), 8.70(2H, d, J=4.8 Hz), 11.7 (1H, brs).

Example 365-[1-Hydroxy-1-(pyrazin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-36)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₅N₃O₂S₂: C, 40.16; H, 2.11; N, 17.56; S, 26.80. Found: C,40.05; H, 2.13; N, 17.35; S, 26.62. NMR(d₆-DMSO) δ: 8.85(1H, s),8.89(1H, s), 9.25(1H, s).

Example 375-[1-Hydroxy-1-(pyridin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-37)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₉H₆N₂O₂S₂: C, 45.36; H, 2.54; N, 11.76; S, 26.91. Found: C,45.16; H, 2.72; N, 11.63; S, 26.79. NMR(d₆-DMSO) δ: 7.49(1H, t, J=4.5Hz), 7.93-8.08(2H, in), 8.66(1H, d, J=4.5 Hz), 12.4(1H, brs).

Example 385-[1-Hydroxy-1-(pyridin-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-38)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₉H₆N₂O₂S₂ 0.1H₂O: C, 44.86; H, 2.86; N, 11.66; S, 26.77.Found: C, 45.02; H, 2.60; N, 11.67; S, 26.71. NMR(d₆-DMSO) δ:7.91-7.96(1H, in), 8.61(1H, d, J=8.4 Hz), 8.81(1H, d, J=5.7 Hz),9.14(1H, d, J=1.8 Hz), 12.2(1H, brs).

Example 395-[1-Hydroxy-1-(pyridin-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-39)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₉H₆N₂O₂S₂ 0.3H₂O: C, 44.36; H, 2.73; N, 11.50; S, 26.31.Found: C, 44.20; H, 2.76; N, 11.57; S, 26.74. NMR(d₆-DMSO) δ: 8.08(2H,t, J=5.4 Hz), 8.85(2H, d, J=5.4 Hz), 12.1 (1H, brs).

Example 405-[1-Hydroxy-1-(5-methyl-1,3,4-oxadiazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-40)

m.p.: 230-237° C. (decomposition) recrystallization solvent: ethanolAnal. Calcd for C₇H₅N₃O₃S₂ 0.1C₆H₈O₇: C, 34.77; H, 2.23; N, 16.01; S,24.43. Found: C, 34.43; H, 2.46; N, 16.47; S, 24.14. NMR(d₆-DMSO) δ:2.55(3H, s), 12.2(1H, brs).

Example 415-[1-Hydroxy-1-(pyrimidin-4-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-41)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₅N₃O₂S₂: C, 40.16; H, 2.11; N, 17.56; S, 26.80. Found: C,39.96; H, 2.05; N, 17.35; S, 26.62. NMR(d₆-DMSO) δ: 8.06(1H, t, J=5.1Hz), 9.10(1H, d, J=5.1 Hz), 9.44 (1H, s).

Example 425-[1-(5-Fluorophenyloxazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-42)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₁₃H₇FN₂O₃S₂: C, 48.44; H, 2.28; F, 5.29; N, 8.69; S, 19.90.Found: C, 48.34; H, 2.12; F, 5.75; N, 8.59; S, 19.79. NMR(d₆-DMSO) δ:7.39(1H, d, J=9.0 Hz), 7.42(1H, d, J=9.0 Hz), 7.88 (1H, d, J=9.0 Hz),7.89(1H, d, J=9.0 Hz), 8.09(1H, s).

Example 43 5-[1-Hydroxy-1-(thiazol-2-yl)]methylene-2-thioxothiazolidin-4-one (Compound I-43)

m.p.: 231° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₇H₄N₂O₂S₃ 0.1C₂H₆O 0.15H₂O: C, 34.37; H, 1.96; N, 11.13; S,38.22. Found: C, 34.73; H, 1.81; N, 11.26; S, 37.90. NMR(d₆-DMSO) δ:8.13(1H, s), 8.19(1H, s).

Example 445-[1-Hydroxy-1-(4-methoxypyridin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-44)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₁₀H₈N₂O₃S₂ 0.1H₂O: C, 44.47; H, 3.06; N, 10.37; S, 23.74.Found: C, 44.30; H, 2.88; N, 10.22; S, 23.82. NMR(d₆-DMSO) δ: 4.11(3H,s), 7.64(1H, m), 7.87(1H, s), 8.87(1H, d, J=6.6 Hz), 13.0(1H, brs).

Example 455-[1-Hydroxy-1-(4-hydroxypyridin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-45)

m.p.: 255° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₉H₆N₂O₃S₂ 0.3CH₄O: C, 42.32; H, 2.75; N, 10.62; S, 24.29.Found: C, 42.41; H, 2.57; N, 10.69; S, 24.03. NMR(d₆-DMSO) δ: 7.29(1H,dd, J=6.3, 2.7 Hz), 7.65(1H, d, J=2.7 Hz), 8.67(1H, d, J=6.3 Hz).

Example 465-[1-(5-Ethoxycarbonylpyrimidin-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-46)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₁₁H₉N₃O₄S₂C, 42.44; H, 2.91; N, 13.50; S, 20.60. Found: C,42.63; H, 2.89; N, 13.20; S, 20.52. NMR(d₆-DMSO) δ: 1.37(3H, t, J=7.2Hz), 4.41(2H, q, J=7.2 Hz), 9.44 (2H, s).

Example 475-[1-(5-Carboxypyrimidin-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-47)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₉H₅N₃O₄S₂ 0.3H₂O: C, 37.00; H, 2.04; N, 14.55; S, 22.60.Found: C, 37.33; H, 1.98; N, 14.51; S, 22.14. NMR(d₆-DMSO) δ: 9.41(2H,s), 13.8(1H, brs).

Example 485-[1-Hydroxy-1-(5-methoxypyridin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-48)

m.p.: >250° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₁₀H₈N₂O₃S₂: C, 44.76; H, 3.01; N, 10.44; S, 23.90. Found: C,44.63; H, 3.04; N, 10.33; S, 23.97. NMR(d₆-DMSO) δ: 3.97(3H, s),7.64(1H, m), 8.10(1H, d, J=9.0 Hz), 8.54(1H, s).

Example 495-[1-Hydroxy-1-(5-hydroxypyridin-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-49)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₉H₆N₂O₃S₂ 0.2C₂H₆O 0.3H₂O: C, 41.99; H, 2.92; N, 10.42; S,23.84. Found: C, 41.87; H, 2.63; N, 10.61; S, 23.52. NMR(d₆-DMSO) δ:7.41(1H, brm), 8.03(1H, brm), 8.38(1H, s), 11.2 (1H, brs), 13.5(1H,brs).

Example 505-[1-Hydroxy-1-(5-methylthiazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-50)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₆N₂O₂S₃ 0.1H₂O: C, 36.94; H, 2.40; N, 10.77; S, 36.97.Found: C, 37.20; H, 2.37; N, 10.76; S, 37.24. NMR(d₆-DMSO) δ: 2.57(3H,s), 7.99(1H, s).

Example 515-[1-Hydroxy-1-(4-methylthiazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-51)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₆N₂O₂S₃: C, 37.20; H, 2.34; N, 10.84; S, 37.23. Found: C,37.00; H, 2.28; N, 10.80; S, 37.01. NMR(d₆-DMSO) δ: 2.51(3H, s),7.81(1H, s).

Example 525-[1-Hydroxy-1-(2-methylthiazol-5-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-52)

m.p.: >250° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₈H₆N₂O₂S₃: C, 37.20; H, 2.34; N, 10.84; S, 37.23. Found: C,37.16; H, 2.39; N, 10.80; S, 37.51. NMR(d₆-DMSO) δ: 2.77(3H, s),8.41(1H, s), 13.5(1H, brs).

Example 535-[1-Hydroxy-1-(2-methyloxazol-4-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-53)

m.p.: 224-226° C. (decomposition) recrystallization solvent: ethanolAnal. Calcd for C₈H₆N₂O₃S₂: C, 39.66; H, 2.50; N, 11.56; S, 26.47.Found: C, 39.69; H, 2.36; N, 11.51; S, 26.31. NMR(d₆-DMSO) δ: 2.52(3H,s), 8.86(1H, s), 13.7(1H, brs).

Example 545-[1-(5-Chlorothiazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-54)

m.p.: 255-270° C. (decomposition) recrystallization solvent: ethanolAnal. Calcd for C₇H₃ClN₂O₂S₃: C, 30.16; H, 1.08; Cl, 12.72; N, 10.05; S,34.50. Found: C, 30.14; H, 1.12; Cl, 12.45; N, 10.03; S, 34.40.NMR(d₆-DMSO) δ: 8.27(1H, s).

Example 555-[1-[5-(3-Cyanopropyloxy)pyridin-2-yl]-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-55)

m.p.: 170° C. (decomposition) recrystallization solvent: ethanol Anal.Calcd for C₁₃H₁₁N₃O₃S₂ 0.55C₂H₆O: C, 48.84; H, 4.16; N, 12.12; S, 18.49.Found: C, 48.79; H, 3.63; N, 12.55; S, 17.50. NMR(d₆-DMSO) δ: 2.52(3H,s), 8.86(1H, s), 13.7(1H, brs). Mass: M/Z=322(M+H)⁺, 320(M−H)⁺.

Example 565-[1-Hydroxy-1-(thiophen-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-56)

m.p.: 225-230° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₈H₅NO₂S₃ 0.25H₂O: C, 38.77; H,2.24; N, 5.68; S, 38.82. Found: C, 38.62; H, 2.01; N, 5.68; S, 39.09.NMR(d₆-DMSO) δ: 7.47(1H, d, J=5.0 Hz), 7.72(1H, dd, J=5.0, 2.6 Hz),8.30(1H, m).

Example 575-[1-Hydroxy-1-(oxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-57)

m.p.: 206-208° C. recrystallization solvent: isopropanol Anal. Calcd forC₇H₄N₂O₃S₂: C, 36.84; H, 1.77; N, 12.27; S, 28.10. Found: C, 36.65; H,1.55; N, 12.14; S, 27.80. NMR(d₆-DMSO) δ: 7.63(1H, s), 8.43(1H, s).

Example 585-[1-Hydroxy-1-(1-methyl-1H-1,2,4-triazol-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-58)

m.p.: 252-256° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₇H₆N₄O₂S₂ 0.125H₂O: C, 34.34; H, 2.57; N, 22.89; S,26.20. Found: C, 34.58; H, 2.52; N, 22.60; S, 25.88. NMR(d₆-DMSO) δ:3.99(3H, s), 8.80(1H, s).

Example 595-[1-Hydroxy-1-(3-methoxymethyloxyisoxazol-5-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-59)

m.p.: 178-180° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₉H₈N₂O₅S₂: C, 37.50; H, 2.80; N, 9.72; S, 22.24. Found:C, 37.46; H, 2.74; N, 9.60; S, 21.84. NMR(d₆-DMSO) δ: 3.45(3H, s),5.33(2H, s), 7.35(1H, s), 12.5(1H,brs).

Example 605-[1-Hydroxy-1-(3-methoxyphenyl)]methylene-2-thioxothiazolidin-4-one(Compound I-60)

m.p.: 182-184° C. recrystallization solvent: n-hexane/ethyl acetateAnal. Calcd for C₁₁H₉NO₃S₂: C, 49.42; H, 3.39; N, 5.24; S, 23.99. Found:C, 49.23; H, 3.37; N, 5.29; S, 23.82. NMR(d₆-DMSO) δ: 3.80(3H, s),6.99-7.40(4H, m).

Example 615-[1-Hydroxy-1-(3-hydroxysoxazol-5-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-61)

m.p.: 235-241° C. (decomposition) recrystallization solvent:n-hexane/ethyl acetate Anal. Calcd for C₇H₄N₂O₄S₂ 0.5C₄H₈O₂ 0.125H₂O: C,37.20; H, 2.86; N, 9.64; S, 22.07. Found: C, 37.17; H, 2.74; N, 9.68; S,21.04. NMR(d₆-DMSO) δ: 7.18(1H, s), 11.3(1H, brs), 12.1(1H, brs).

Example 625-[1-[3-(2-Cyanobenzyloxy)isoxazol-5-yl]-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-62)

m.p.: 255-260° C. (decomposition) recrystallization solvent: ethylacetate/methanol Anal. Calcd for C₁₅H₉N₃O₄S₂ 0.5C₄H₈O₂ 0.125H₂O: C,50.13; H, 2.52; N, 11.69; S, 17.84. Found: C, 50.12; H, 2.52; N, 11.64;S, 17.95. NMR(d₆-DMSO) δ: 5.47(2H, s), 7.34(1H, s), 7.61(1H, m),7.78(2H, d, J=4.2 Hz), 7.94(1H, d, J=7.8 Hz).

Example 635-[1-(4,5-Dimethyloxazol-2-yl]-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-63)

m.p.: 256-259° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₉H₈N₂O₃S₂ C, 42.18; H, 3.15; N, 10.93; S, 25.02. Found:C, 42.35; H, 3.20; N, 10.66; S, 24.88. NMR(d₆-DMSO) δ: 2.16(3H, s),2.37(3H, s).

Example 645-[1-[3-(3-Cyanopropyloxy)isoxazol-5-yl]-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-64)

m.p.: 197-199° C. recrystallization solvent: isopropanol Anal. Calcd forC₁₁H₉N₃O₄S₂: C, 42.44; H, 2.91; N, 13.50; S, 20.60. Found: C, 42.53; H,2.86; N, 13.23; S, 20.45. NMR(d₆-DMSO) δ: 2.07(2H, m), 2.66(2H, t, J=7.2Hz), 4.23(2H, t, J=6.0 Hz), 7.27(1H, s).

Example 655-[1-hHdroxy-1-(5-methyloxazol-2-yl)]methylene-3-methyl-2-thioxothilazolidin-4-one(Compound I-65)

m.p.: 192-195° C. (decomposition) recrystallization solvent: isopropanolNMR(d₆-DMSO) δ: 2.40(3H, s), 3.31(3H, s), 7.24(1H, s).

Example 665-[1-[3-(3-Cyanopropyloxy)]phenyl-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-66)

m.p.: 125-127° C. recrystallization solvent: isopropanol Anal. Calcd forC₁₄H₁₂N₂O₃S₂ 0.125H₂O: C, 51.75; H, 3.83; N, 8.68; S, 19.88. Found: C,51.88; H, 3.75; N, 8.71; S, 20.05. NMR(d₆-DMSO) δ: 2.04(2H, m), 2.67(2H,t, J=7.0 Hz), 4.09(2H, t, J=7.0 Hz), 7.14(1H, d, J=7.8 Hz), 7.21(1H, s),7.22(1H, d, J=7.8 Hz), 7.43(1H, t, J=7.8 Hz).

Example 675-[1-[3-(2-Cyanobenzyloxy)]phenyl-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-67).

m.p.: 174-176° C. recrystallization solvent: isopropanol Anal. Calcd forC₁₈H₁₂N₂O₃S₂: C, 58.68; H, 3.28; N, 7.60; S, 17.41. Found: C, 58.62; H,3.40; N, 7.69; S, 17.01. NMR(d₆-DMSO) δ: 5.30(2H, s), 7.22(1H, d, J=8.0Hz), 7.29(1H, d, J=8.0 Hz), 7.35(1H, s), 7.44(1H, t, J=8.0 Hz), 7.59(1H,m), 7.75(1H, m), 7.77(1H, m), 7.93 (1H, d, J=7.8 Hz).

Example 685-[1-(5-Ethyloxazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-68)

m.p.: 201-204° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₉H₈N₂O₃S₂ 0.25H₂O: C, 41.44; H, 3.29; N, 10.74; S,24.59. Found: C, 41.18; H, 2.98; N, 10.58; S, 24.38. NMR(d₆-DMSO) δ:1.23(3H, t, J=7.5 Hz), 2.79(2H, q, J=7.5 Hz), 7.35 (1H, s).

Example 695-[1-Hydroxy-1-(5-methoxyoxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-69)

m.p.: 191-195° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₈H₆N₂O₄S₂ 0.125H₂O: C, 36.88; H, 2.42; N, 10.75; S,24.62. Found: C, 36.68; H, 2.69; N, 10.88; S, 24.73. NMR(d₆-DMSO) δ:4.02(3H, s), 6.88(1H, s).

Example 705-[1-(5-Ethoxyoxazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-70)

m.p.: 195-198° C. recrystallization solvent: isopropanol Anal. Calcd forC₉H₈N₂O₄S₂ 0.17C₃H₈O 0.125H₂O: C, 40.26; H, 2.98; N, 9.89; S, 22.63.Found: C, 40.41; H, 3.20; N, 9.81; S, 22.70. NMR(d₆-DMSO) δ: 1.38(3H, t,J=6.6 Hz), 4.31(2H, q, J=6.6 Hz), 6.89 (1H, s).

Example 715-[1-Hydroxy-1-(4-methyloxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-71)

m.p.: 203-205° C. recrystallization solvent: isopropanol Anal. Calcd forC₈H₆N₂O₃S₂: C, 39.66; H, 2.50; N, 11.56; S, 26.47. Found: C, 39.64; H,2.57; N, 11.32; S, 25.95. NMR(d₆-DMSO) δ: 2.22(3H, d, J=1.5 Hz),8.17(1H, d, J=1.5 Hz).

Example 725-[1-Hydroxy-1-(5-propyloxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-72)

m.p.: 188-192° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₁₀H₁₀N₂O₃S₂: C, 44.43; H, 3.73; N, 10.36; S, 23.72.Found: C, 44.26; H, 3.59; N, 10.30; S, 24.10. NMR(d₆-DMSO) δ: 0.94(3H,t, J=7.2 Hz), 1.66(2H, m), 2.75(2H, t, J=7.2 Hz), 7.38(1H, s).

Example 735-[1-Hydroxy-1-(4-methylfuran-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-73)

m.p.: 242-245° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₉H₇NO₃S₂: C, 44.80; H, 2.92; N, 5.80; S, 26.58. Found:C, 44.53; H, 2.80; N, 5.83; S, 26.50. NMR(d₆-DMSO) δ: 2.06(3H, s),7.38(1H, s), 7.93(1H, s), 13.6(2H, brs).

Example 745-[1-(4-Chlorothiophen-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-74)

m.p.: 228-232° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₈H₄ClNO₂S₃: C, 34.59; H, 1.45; Cl, 12.76; N, 5.04; S,34.63. Found: C, 34.60; H, 1.37; Cl, 12.70; N, 5.09; S, 34.35.NMR(d₆-DMSO) δ: 7.75(1H, s), 8.63(1H, s), 12.4(1H, brs).

Example 755-[1-[4-(3-Cyanopropyloxy)]phenyl-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-75)

m.p.: 172-177° C. recrystallization solvent: isopropanol Anal. Calcd forC₁₄H₁₂N₂O₃S₂ 0.38H₂O: C, 51.40; H, 3.93; N, 8.56; S, 19.60. Found: C,51.47; H, 3.75; N, 8.49; S, 20.05. NMR(d₆-DMSO) δ: 2.06(2H, m), 2.67(2H,m), 4.13(2H, m), 7.10(2H, d, J=8.8 Hz), 7.70(2H, d, J=8.8 Hz).

Example 765-[1-Hydroxy-1-(5-methyl-4,5-dihydrooxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-76)

m.p.: 184-185° C. recrystallization solvent: diisopropyl ether Anal.Calcd for C₈H₈N₂O₃S₂ 1.25H₂O: C, 36.01; H, 3.97; N, 10.50; S, 24.04.Found: C, 36.28; H, 3.73; N, 10.38; S, 23.84. NMR(d₆-DMSO) δ: 1.02(3H,d, J=6.6 Hz), 3.14(2H, t, J=6.0 Hz), 3.75 (1H, m), 8.74(1H, brs),9.36(1H, brs).

Example 775-[1-[2-(3-Cyanopropyloxy)]phenyl-1-hydroxy-]methylene-2-thioxothiazolidin-4-onesodium salt (Compound I-77)

Foamy Powder Anal. Calcd for C₁₄H₁₁N₂O₃S₂Na₁ ₂H₂O 0.125C₄H₈O₂: C, 46.27;H, 3.72; N, 7.49; Na, 7.38; S, 17.16. Found: C, 46.31; H, 3.50; N, 7.29;Na, 7.40; S, 16.90. NMR(d₆-DMSO) δ: 2.11(2H, m), 2.74(2H, t, J=7.2 Hz),4.20(2H, t, J=7.2 Hz), 7.00-7.80(4H, m).

Example 785-[1-Hydroxy-1-(5-methyl-1H-1,2,4-triazol-3-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-78)

m.p.: >300° C. (decomposition) recrystallization solvent: methanol Anal.Calcd for C₇H₆N₄O₂S₂: C, 34.70; H, 2.50; N, 23.12; S, 26.47. Found: C,34.54; H, 2.42; N, 22.86; S, 26.78. NMR(d₆-DMSO) δ: 3.16(3H, s),13.8(3H, brs).

Example 795-[1-Hydroxy-1-[(4-hydroxymethyl-5-methyl)oxazol-2-yl)]methylene-2-thioxothiazolidin-4-one(Compound I-79)

m.p.: 145-151° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₉H₈N₂O₄S₂ 0.1C₃H₈O: C, 40.35; H, 3.30; N, 9.96; S,22.80. Found: C, 40.28; H, 2.94; N, 9.63; S, 22.19. NMR(d₆-DMSO) δ:2.43(3H, s), 4.55(2H, s).

Example 805-[1-[(5-Ethoxy-4-ethoxycarbonyl)oxazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-80)

m.p.: 200-205° C. (decomposition) recrystallization solvent: isopropanolAnal. Calcd for C₁₂H₁₂N₂O₆S₂: C, 41.85; H, 3.51; N, 8.13; S, 18.62.Found: C, 41.68; H, 3.48; N, 8.02; S, 18.41. NMR(d₆-DMSO) δ: 1.27(3H, t,J=7.2 Hz), 1.41(3H, t, J=7.2 Hz), 4.26 (2H, q, J=7.2 Hz), 4.58(2H, q,J=7.2 Hz).

Example 815-[1-(4-Carboxy-5-ethoxyoxazol-2-yl)-1-hydroxy]methylene-2-thioxothiazolidin-4-one(Compound I-81)

m.p.: >300° C. (decomposition) recrystallization solvent:isopropanol/n-hexane NMR(d₆-DMSO) δ: 1.38(3H, t, J=7.0 Hz), 4.49(2H, q,J=7.0 Hz), 12.7 (1H, brs).

Example 82 5-[(]-Furan-2-yl)-1-hydroxy]methylene-imidazolidine-2,4-dione(Compound I-82)

(1) To a solution of hydantoin (3.0 g, 30 mmol) in DME (120 ml) wereadded di-tert-butylcarbonate (27 g, 126 mmol), DMAP (67 mg, 0.55 mmol),and trietylamine (3.1 g, 30.6 mmol) sequentially at room temperature.The reaction mixture was allowed to stand at room temperature overnightand concentrated under reduced pressure. Water was added to the residueand the solution was extracted with ethyl acetate. The extract waswashed with water, dried, and concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography. Fractionationeluted by chloroform/ethyl acetate (v/v, 9/1) was concentrated to give1,3-di-tert-butoxycarbonylimidazolidine-2,4-dione (810 mg, 9%) as a oil.

NMR(CDCl₃) δ: 1.56(9H, s), 1.58(9H, s), 4.23(2H, s).

(2) To a solution of above obtained compound (300 mg, 1 mmol) in THF (10ml) was added dropwise THF solution of lithium bis(trimethylsilyl)amide(1M, 1.5 mL, 1.5 mmol) at −78-−68° C. After the reaction mixture wasstirred at the same temperature for 30 min, a solution of 2-furoylchloride (0.26 g, 2 mmol) in THF (3 ml) was added thereto. The reactionmixture was stirred at the same temperature for 30 min and at roomtemperature for 2.5 h. The reaction mixture was poured into ice-watercontaining a aqueous solution of 1 mol/L citric acid (2 mL), extractedtwo times with ethyl acetate, washed with a saturated aqueous solutionof sodium hydrogen carbonate and brine, and dried. The solvent wasevaporated and the residual oil was powdered by n-hexane to give5-[(1-furan-2-yl)-1-hydroxy]methylene-1,3-(di-tert-butoxycarbonyl)imidazolidine-2,4-dione(280 mg, 71%).

NMR(CDCl₃) δ: 1.44(9H, s), 1.56(9H, s), 5.78(1H, s), 6.68(1H, dd, J=1.5,3.9 Hz), 7.48(1H, d, J=3.9 Hz), 7.60(1H, J=1.5 Hz).

(3) The above compound (100 mg, 0.25 mmol) was heated at 120° C. withoutsolvent. After cooling, the residue was washed with ethanol and filteredto give the title compound (25 mg, 51%).

m.p.: 220-222° C. (decomposition) recrystallization solvent: ethanolAnal. Calcd for C₈H₆N₂O₄ 0.1H₂O: C, 49.04; H, 3.19; N, 14.30. Found: C,48.94; H, 3.18; N, 14.61. NMR(d₆-DMSO) keto-type δ: 5.69(1H, s),6.84(1H, d, J=3.6 Hz), 7.74(1H, d, J=3.6 Hz),8.16(1H, s), 8.24(1H, s),11.0(1H, brs).

Experiment Example

The later-mentioned experimental examples were done by using theabove-mentioned compound.

Experiment Example 1 Inhibitory Activity Against HCV RNA-Dependent RNAPolymerase

(1) Preparation of Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase

It was collected several cDNA clones of HCV RNA-dependent RNA polymerasefrom plasma of people infected with HCV, RNA-dependent RNA polymerasewas expressed by using insect cell or E. coli from these clones.RNA-dependent RNA polymerase in cell extract was purified byanion-exchange chromatography, heparin-affinity chromatography, polyU-affinity chromatography, cation-exchange chromatography, gelfiltration chromatography, and the like. The preparation was done atabout 4° C. under low temperature condition, as solution dissolvingenzyme was used Tris buffer (pH 7.5) containing ethylenediaminetetraacetic acid (1 mM), dithiothreitol (10 mM), and glycerol (20%). Thepurified enzyme was kept at 4° C. or −20° C. until it was used forassay.

(2) Method of HCV RNA-Dependent RNA Polymerase Assay

{circle around (1)} In polypropylene vessel was added buffer I*¹⁾(10.5μL) containing Tris-HCl (100 mM, pH 7.5), magnesium chloride (25 mM),dithiothreitol (5 mM), potassium chloride (125 mM), ethylenediaminetetraacetic acid (5 mM), and then were added poly(A)*²⁾ aqueous solution(100 μg/mL, 10.5 μL), oligo(U)_(12*) ³⁾ aqueous solution (10 μg/mL, 10.5μL), and water (8 μL), and the mixture was mixed slowly.

*1) All of water used as experimental material in enzyme reaction werecarried out inactivation treatment of Rnase with diethylpyrocarbonate.The inactivation treatment with diethylpyrocarbonate was carried out asfollows, 1) diethylpyrocarbonate (0.1 g) was dissolved in de-ionizedwater (100 mL), 2) the solution was stood at 37° C. for 24 h, 3) kept inautoclave at 120° C. for 30 min.

*2) Poly(A) is single strand polynucleotide composed with only adenylicacid. It was used as template.

*3) Oligo(U)₁₂ is single strand oligonucleotide composed with only 12element of uridylic acid. It was used as primer.

{circle around (2)} Next, to the mixture was added a solution (10.5 μL)of RNA-dependent RNA polymerase, and preincubation was carried out at25° C. for 60 min.

{circle around (3)} A solution (50 μL) preincubated described in {circlearound (2)} was added into 96-wells microtiter plate divided testcompound (5.26 μL per well) dissolved with dimethylsulfoxide or water.

{circle around (4)} Moreover, to the mixture was added a mixed solution(50 μL) of water (39.4 μL) and buffer II (10.6 μL) containing Tris-HCl(100 mM, pH 7.5), magnesium chloride (25 mM), dithiothreitol (5 mM),potassium chloride (125 mM), ethylenediamine tetraacetic acid (5 mM),and UTP⁴⁾ (2.1 μM, containing 1 μCi³H-UTP) and the mixture was mixed,and the enzyme reaction was carried out at 25° C. for 30 min.

*4) UTP is uridine triphosphate. It was used as substrate.

{circle around (5)} When the enzyme reaction was passed for 30 min, tothe mixture was added a aqueous solution (50 mM, 50 μL) ofethylenediamine tetraacetic acid disodium and the enzyme reaction wasstopped.

{circle around (6)} Next, after all volume of sample of {circle around(5)} was transferred on filter introduced diethylaminoethyl group(henceforth shortening as DEAE-filter mat) by using cell harvester, wascarried the washing twice with sodium phosphate buffer (0.25 M, pH 7.0)for 10 sec and the washing once with deionized water for 10 sec.

{circle around (7)} After the washing, DEAE-filter mat was dried at 95°C. for 15 min and sealed together with liquid scintillator (10 mL) intosample bag.

{circle around (8)} Radioactivity was measured by using scintillationcounter.

{circle around (9)} The percentage of inhibition was calculated byreplacing the measured value of radioactivity (unit; ccpm) into thefollowing expression.

The percentage of inhibition=100−(the measured value in presence of testcompound−the measured value in absence of enzyme)÷(the measured value inabsence of test compound−the measured value in absence of enzyme)×100.

{circle around (10)} The concentration of test compound inhibiting 50%(IC₅₀) was obtained from the percentage of inhibition calculated in{circle around (9)} and the used concentration of test compoundinhibiting.

In case of the percentage of inhibition is A % when α μg/mL of thecompound is used and the percentage of inhibition is B % when β μg/ml ofthe compound is used, IC₅₀ was obtained from the following expression.Provided that it is theorized as A≧50>B.

IC ₅₀(unit; μg/mL)=10^({(50−B)/(A−B)×log α−log β)+log β})

Experiment Example 2 Inhibitory Activity Against BVDV RNA-Dependent RNAPolymerase

Inhibitory activity against RNA-dependent RNA polymerase (RdRp) ofbovine virus diarrhea virus (BVDV) was experimented too in the same wayin experiment example 1.

The results of experiment example 1 and experiment example 2 are shownin Table 1.

TABLE 1 Experimental example Experimental example 1 2 IC₅₀ for HCV RdRpIC₅₀ for BVDV RdRp Compound Number (μg/mL) (μg/mL) I-1 0.25 2.5 I-2 0.9018 I-22 4.9 37 I-27 1.6 18 I-28 7.1 24 I-29 1.8 27 I-30 6.8 32 I-32 3.237 I-34 0.92 14 I-35 1.4 34 I-36 7.6 38 I-37 3.0 36 I-40 2.0 5.3

Formulation Example

The following formulation examples are provided to further illustratethe present invention and are not to be construed as limiting the scopethereof. The tern “active ingredient” used herein means a compound usedin the present invention, a tautomer, a prodrug, a pharmaceuticalacceptable salt, or a salt thereof.

Formulation Example 1

Hard gelatin capsules are prepared using of the following ingredients:

Dose (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared using of the following ingredients:

Dose (mg/tablet) Active ingredient 250 Cellulose, microcrystals 400Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg.

Formulation Example 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22(chlorodifluoromethane) 74.00 Total 100.00

The active compound is mixed with ethanol and the admixture is added toa portion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the reminder of the propellant. The valveunits are then fitted to the container.

Formulation Example 4

Tablets, each containing 60 mg of active ingredient, are made asfollows.

Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35 mgPolyvinylpyrrolidone (as 10% solution in water) 4 mg Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve, and the mixed thoroughly. The aqueous solutioncontaining polyvinylpyrrolidone is mixed with the resultant powder, andthe admixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C. and passed through a No. 18mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate,and talc, previously passed through No. 60 mesh U.S. sieve, are thenadded to the granules which, after mixing, are compressed on a tabletmachine to yield tablets each weighing 150 mg.

Formulation Example 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

Active ingredient 80 mg Starch 59 mg Microcrystals cellulose 59 mgMagnesium stearate 2 mg Total 200 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation Example 6

Suppository, each containing 225 mg of active ingredient, are made asfollows:

Active ingredient  225 mg Saturated fatty acid glycerides 2000 mg Total2225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7

Suspensions, each containing 50 mg of active ingredient per 5 mL dose,are made as follows:

Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mL Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified waterto total 5 mL

The active ingredient is passed through a No. 45 U.S. sieve, and mixedwith the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 8

An intravenous formulation may be prepared as follows:

Active ingredient 100 mg Isotonic saline 1000 mL

The solution of the above ingredients is generally administeredintravenously to a subject at a rate of 1 mL per minute.

Industrial Applicability

The compound of the formula (I) or (II) exhibits an inhibitory activityagainst a nucleic acid polymerase, in detail an inhibitory activityagainst a RNA-dependent RNA polymerase. Therefore, hepatitis C virus andthe like can be treated with an inhibitory agent against a RNA-dependentRNA polymerase which contains the compound of the formula (I) or (II).

What is claimed is:
 1. A method of treating hepatitis C comprisingadministration of a treating agent against hepatitis C which contains asan active ingredient a compound of the formula (I), a tautomer, aprodrug, a pharmaceutically acceptable salt, or a solvate thereof:

wherein R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R² and R³ taken together withthe adjacent carbon atom form an optionally substituted heterocyclicgroup having one or more of oxo and/or thioxo.
 2. The method asdescribed in claim 1 wherein R¹ is optionally substituted heteroaryl oroptionally substituted aryl; R² and R³ taken together with the adjacentcarbon atom form a group of the formula (A):

wherein A¹ and A³ are each independently oxygen atom or sulfur atom; A²and A⁴ are each independently —O—, —S—, or —NR⁴— wherein R⁴ is hydrogen,alkyl, acyl, optionally substituted aryl, or optionally substitutedaralkyl.
 3. A treating agent against hepatitis C which contains as anactive ingredient a compound of the formula (I), a tautomer, a prodrug,a pharmaceutically acceptable salt, or a solvate thereof:

wherein R¹ is optionally substituted heteroaryl or optionallysubstituted aryl; R² and R³ taken together with the adjacent carbon atomform a group of the formula (A):

wherein A¹ is oxygen atom; A² is —NH—; A³ and A⁴ are —S—.
 4. A compoundof the formula (II):

wherein R¹ is optionally substituted carbocyclic group or optionallysubstituted heterocyclic group; A¹ and A³ are each independently oxygenatom or sulfur atom; A² is —NR⁴— wherein R⁴ is hydrogen, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedaryl, or optionally substituted aralkyl, provided that when R¹ isoptionally substituted aryl, R⁴ is hydrogen or optionally substitutedalkyl; A⁴ is —S—; and provided that the following compounds are excludedwherein A¹ is oxygen atom, A² is —NEt-, A³ is sulfur atom, and R¹ is4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl,4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl;A¹ is oxygen atom, A² is —NH—, A³ is sulfur atom, and R¹ is2-thiocarboxyphenyl or 2-carboxyphenyl; and A¹ is oxygen atom, A² is—NH—, A³ is oxygen atom, and R¹ is 2-carboxyphenyl; a tautomer, aprodrug, a pharmaceutically acceptable salt, or a solvate thereof.
 5. Acompound of claim 4 wherein R¹ is optionally substituted heteroaryl; atautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof.
 6. A compound of claim 4 wherein R¹ is non-substitutedheteroaryl or heteroaryl substituted with alkyl, alkoxy, hydroxy,halogen, trityl, alkoxyalkoxy, cyanoallylalkoxy, cyanoalkoxy,hydroxyalkyl, cyanoalkyl, carboxy or alkoxycarbonyl; a tautomer, aprodrug, a pharmaceutically acceptable salt, or a solvate thereof.
 7. Acompound of claim 5 wherein R¹ is optionally substituted 5-memberedheteroaryl; a tautomer, a prodrug, a pharmaceutically acceptable salt,or a solvate thereof.
 8. A compound of claim 5 wherein R¹ is optionallysubstituted furyl, optionally substituted thienyl, optionallysubstituted pyrrolyl, optionally substituted imidazolyl, optionallysubstituted oxazolyl optionally substituted isoxazolyl, optionallysubstituted triazolyl, optionally substituted oxadiazolyl, optionallysubstituted tetrazolyl, optionally substituted pyridyl, optionallysubstituted benzofuryl, optionally substituted pyrimidinyl, optionallysubstituted pyrazinyl, or optionally substituted thiazolyl; a tautomer,a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 9.A compound of claim 4 wherein R¹ is optionally substituted aryl; atautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof.
 10. A compound of claim 4 wherein A² is —NH—; a tautomer, aprodrug, a pharmaceutically acceptable salt, or a solvate thereof.
 11. Acompound of claim 4 wherein A¹ is oxygen atom; A³ is sulfur atom; atautomer, a prodrug, a pharmaceutically acceptable salt, or a solvatethereof.
 12. A compound of claim 4 wherein A¹ is oxygen atom; A² is—NH—; A³ is sulfur atom; A⁴ is —S—; a tautomer, a prodrug, apharmaceutically acceptable salt, or a solvate thereof.
 13. Apharmaceutical composition which contains as an active ingredient acompound of claim 4, a tautomer, a prodrug, a pharmaceuticallyacceptable salt, or a solvate thereof.
 14. A pharmaceutical compositionof claim 13 as a treating agent against hepatitis C.
 15. Apharmaceutical composition of claim 13 as an anti-hepatitis C virusagent.
 16. A pharmaceutical composition of claim 13 as a nucleic acidpolymerase inhibitor.
 17. A pharmaceutical composition of claim 13 as aRNA-dependent RNA polymerase inhibitor.
 18. A method of treatinghepatitis C comprising administration of a treating agent againsthepatitis C of claim 3.